PPAR-alpha and PPAR-gamma activators induce cholesterol removal from humanmacrophage foam cells through stimulation of the ABCA1 pathway

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors t hat regulate lipid and glucose metabolism and cellular differentiation. PPA R-alpha and PPAR-gamma are both expressed in human macrophages where they e xert anti-inflammatory effects. The activation of PPAR-gamma may promote fo am-cell formation by inducing expression of the macrophage scavenger recept or CD36. This prompted us to investigate the influence of different PPAR- a ctivators on cholesterol metabolism and foam-cell formation of human primar y and THP-1 macrophages. Here we show that PPAR-alpha and PPAR-gamma activa tors do not influence acetylated low density lipoprotein-induced foam-cell formation of human macrophages. In contrast, PPAR-alpha and PPAR-gamma acti vators induce the expression of the gene encoding ABCA1, a transporter that controls apoAI-mediated cholesterol efflux from macrophages. These effects are likely due to enhanced expression of liver-x-receptor alpha, an oxyste rol-activated nuclear receptor which inducer ABCA1- promoter transcription. Moreover, PPAR-alpha and PPAR-gamma activators increase apoAI-induced chol esterol efflux from normal macrophages. In contrast, PPAR-alpha or PPAR-gam ma activation does not influence cholesterol efflux from macrophages isolat ed from patients with Tangier disease, which is due to a genetic defect in ABCA1. Here we identify a regulatory role for PPAR-alpha and PPAR-gamma in the first steps of the reverse-cholesterol-transport pathway through the ac tivation of ABCA1-mediated cholesterol efflux in human macrophages.